1. Field of the Invention
This invention relates to dibenzofurancarboxamides derivatives which selectively bind to brain dopamine receptor subtypes. More specifically, it relates to N-alkylaminodibenzofurancarboxamides and to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in the treatment or prevention of various neuropsychochological disorders such as schizophrenia and other central nervous system diseases.
2. Description of the Related Art
The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D.sub.2 receptors in the striatal region of the brain. The dopamine D.sub.3 receptor subtype has recently been identified (Sokoloff et al., Nature, 347: 146 (1990). Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D.sub.3 receptor may play a major role in the etiology of schizophrenia. Selective D.sub.3 antagonists may be effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics. Compounds of the present invention demonstrate high affinity and selectivity in binding to the D.sub.3 receptor subtype. They may be of potential use in treatment of schizophrenia, psychotic depression and mania. Other dopamine-mediated diseases such as Parkinsonism and tardive dyskinesias may also be treated directly or indirectly by modulation of D.sub.3 receptors.
Furthermore, compounds of this invention may be useful in treatment of depression, memory-impairment or Alzheimer's disease by modulation of D.sub.3 receptors which selectively exist in limbic area known to control emotion and cognitive functions. The compounds of the present invention are also useful for the treatment of other disorders which respond to dopaminergic blockade such as substance abuse (Caine and Koob, Science, 260: 1814 (1993)) and obsessive compulsive disorder (Goodman et al., Clin. Psychopharmacol., 7: 35 (1992)). The interaction of N-alkylaminodibenzofurancarboxamides with dopamine receptor subtypes is described. This interaction results in the pharmacological activities of these compounds.
U.S. Pat. No. 5,395,835 discloses N-aminoalkyl-2-napthalamides said to have affinity for dopamine D.sub.3 receptors. The novel compounds of claim 1 of the present invention differ significantly from this prior art in that they possess a dibenzofurancarboxamide substructure.
Murray et al., in Bioorg. Med. Chem. Let., 5: 219 (1995), describes 4-carboxamido-biphenyls said to have affinity for dopamine D.sub.3 receptors.